Archives of Pharmacal Research

The molecular chaperone heat shock protein 90 (HSP90) regulates multiple crucial signalling pathways in cancer by driving the maturation of key signalling components, thereby playing a crucial role in tumorigenesis and drug resistance in cancer. Inhibition of HSP90 results in metastable conformational collapse of its client proteins and their proteasomal degradation. Considerable efforts have been devoted to the development of small-molecule inhibitors targeting HSP90, and more than 20 inhibitors have been evaluated in clinical trials for cancer therapy...

The relationship between schizophrenia (SCZ) and cancer development remains controversial. Based on the disease-gene association platform, it has been revealed that tumor necrosis factor receptor (TNFR) could be an important mediatory factor in both cancer and SCZ development. TNF-α also increases the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in the development of SCZ and tumor, but the role of TNFR in mediating the association between the two diseases remains unclear...

Sarcopenia is a multifactorial condition characterized by loss of muscle mass. It poses significant health risks in older adults worldwide. Both pharmacological and non-pharmacological approaches are reported to address this disease. Certain dietary patterns, such as adequate energy intake and essential amino acids, have shown positive outcomes in preserving muscle function. Various medications, including myostatin inhibitors, growth hormones, and activin type II receptor inhibitors, have been evaluated for their effectiveness in managing sarcopenia...

Sialyllactoses (SLs) primarily include sialylated human milk oligosaccharides (HMOs) and bovine milk oligosaccharides (BMOs). First, the safety assessment of 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL) revealed low toxicity in various animal models and human participants. SLs constitute a unique milk component, highlighting the essential nutrients and bioactive components crucial for infant development, along with numerous associated health benefits for various diseases. This review explores the safety, biosynthesis, and potential biological effects of SLs, with a specific focus on their influence across various physiological systems, including the gastrointestinal system, immune disorders, rare genetic disorders (such as GNE myopathy), cancers, neurological disorders, cardiovascular diseases, diverse cancers, and viral infections, thus indicating their therapeutic potential...

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats...

Astragali Radix (A. Radix) is the dried root of Astragalus membranaceus var. mongholicus (Bge) Hsiao or Astragalus membranaceus (Fisch.) Bge., belonging to the family Leguminosae, which is mainly distributed in China. A. Radix has been consumed as a tonic in China for more than 2000 years because of its medicinal effects of invigorating the spleen and replenishing qi. Currently, more than 400 natural compounds have been isolated and identified from A. Radix, mainly including saponins, flavonoids, phenylpropanoids, alkaloids, and others...

Microbiota-derived catabolism of nutrients is closely related to ulcerative colitis (UC). The level of indole-3-acetic acid (IAA), a microbiota-dependent metabolite of tryptophan, was decreased significantly in the feces of UC patients. Thus supplementation with IAA could be a potential therapeutic method for ameliorating colitis. In this work, the protective effect of supplementation with IAA on dextran sulfate sodium (DSS)-induced colitis was evaluated, and the underlying mechanism was elucidated. The results indicated that the administration of IAA significantly relieved DSS-induced weight loss, reduced the disease activity index (DAI), restored colon length, alleviated intestinal injury, and improved the intestinal tight junction barrier...

Type 2 diabetes mellitus (T2DM) is a persistent metabolic disorder marked by deficiencies in insulin secretion and/or function, affecting various tissues and organs and leading to numerous complications. Mitochondrial biogenesis, the process by which cells generate new mitochondria utilizing existing ones plays a crucial role in energy homeostasis, glucose metabolism, and lipid handling. Recent evidence suggests that promoting mitochondrial biogenesis can alleviate insulin resistance in the liver, adipose tissue, and skeletal muscle while improving pancreatic β-cell function...

Gymnopilus orientispectabilis, also known as "big laughter mushroom," is a hallucinogenic poisonous mushroom that causes excessive laughter upon ingestion. From the fruiting bodies of G. orientispectabilis, eight lanostane-type triterpenoids (1-8), including seven novel compounds: gymnojunols A-G (2-8), were isolated. The chemical structures of these new compounds (2-8) were determined by analyzing their 1D and 2D NMR spectra and HR-EISMS, and their absolute configurations were unambiguously assigned by quantum chemical ECD calculations and a computational method coupled with a statistical procedure (DP4+)...

Insulin resistance (IR) is a key factor in the pathogenesis of disrupted glucose metabolism. Although the extract of Glycyrrhiza glabra has shown significant hypoglycemic activity, its bioactive components remain to be identified, and their mechanisms of action, especially on hepatocyte glucose metabolism, are yet to be explored. In the present study, the primary compounds from Glycyrrhiza glabra [named prenylated flavonoid fractions (PFFs)] have been identified and their chemical structures have been elucidated...

The gut microbiota that exists in the human gastrointestinal tract is incredibly important for the maintenance of general health as it contributes to multiple aspects of host physiology. Recent research has revealed a dynamic connection between the gut microbiota and the central nervous system, that can influence neurodegenerative diseases (NDs). Indeed, imbalances in the gut microbiota, or dysbiosis, play a vital role in the pathogenesis and progression of human diseases, particularly NDs. Herbal medicine has been used for centuries to treat human diseases, including NDs...

Aschantin, a tetrahydrofurofuran lignan with a 1,3-benzodioxole group derived from Flos Magnoliae, exhibits antioxidant, anti-inflammatory, cytotoxic, and antimicrobial activities. This study compared the metabolic profiles of aschantin in human, dog, mouse, and rat hepatocytes using liquid chromatography-high-resolution mass spectrometry. The hepatic extraction ratio of aschantin among the four species was 0.46-0.77, suggesting that it undergoes a moderate-to-extensive degree of hepatic metabolism. Hepatocyte incubation of aschantin produced 4 phase 1 metabolites, including aschantin catechol (M1), O-desmethylaschantin (M2 and M3), and hydroxyaschantin (M4), and 14 phase 2 metabolites, including O-methyl-M1 (M5 and M6) via catechol O-methyltransferase (COMT), six glucuronides of M1, M2, M3, M5, and M6, and six sulfates of M1, M2, M3, M5, and M6...

Pitavastatin, a potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemia and mixed dyslipidemia. Hepatic uptake of pitavastatin is predominantly occupied by the organic anion transporting polypeptide 1B1 (OATP1B1) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene, which is a polymorphic gene that encodes OATP1B1. SLCO1B1 genetic polymorphism significantly alters the pharmacokinetics of pitavastatin. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict pitavastatin pharmacokinetics according to SLCO1B1 genetic polymorphism...

The emergence of antibody-drug conjugates (ADCs) as a potential therapeutic avenue in cancer treatment has garnered significant attention. By combining the selective specificity of monoclonal antibodies with the cytotoxicity of drug molecules, ADCs aim to increase the therapeutic index, selectively targeting cancer cells while minimizing systemic toxicity. Various ADCs have been licensed for clinical usage, with ongoing research paving the way for additional options. However, the manufacture of ADCs faces several challenges...

Gastric cancer (GC) is one of the most prevalent malignancies in the world, with a high mortality rate in both women and men. Conventional treatments, like chemotherapy, radiotherapy and surgery, are facing some drawbacks like acquired drug resistance and various side effects, leading to cancer recurrence and increased morbidity; thus, development of novel approaches in targeted therapy would be very beneficial. Exosomes, extracellular vesicles with a size distribution of sub-150 nm, interplay in physiological and pathophysiological cell-cell communications and can pave the way for targeted cancer therapy...

Ocular diseases are a growing global concern and have a significant impact on the quality of life. Cataracts, glaucoma, age-related macular degeneration, and diabetic retinopathy are the most prevalent ocular diseases. Their prevalence and the global market size are also increasing. However, the available pharmacotherapy is currently limited. These diseases share common pathophysiological features, including neovascularization, inflammation, and/or neurodegeneration. Histone deacetylases (HDACs) are a class of enzymes that catalyze the removal of acetyl groups from lysine residues of histone and nonhistone proteins...

Pantoprazole is used to treat gastroesophageal reflux disease (GERD), maintain healing of erosive esophagitis (EE), and control symptoms related to Zollinger-Ellison syndrome (ZES). Pantoprazole is mainly metabolized by cytochrome P450 (CYP) 2C19, converting to 4'-demethyl pantoprazole. CYP2C19 is a genetically polymorphic enzyme, and the genetic polymorphism affects the pharmacokinetics and/or pharmacodynamics of pantoprazole. In this study, we aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of pantoprazole in populations with various CYP2C19 metabolic activities...

The post-transcriptional processing of N6 -methyladenosine (m6 A)-modified mRNA by YTH domain-containing family protein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequently upregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells. The WW domain of PIN1 interacted with YTHDF1 in a phosphorylation-dependent manner...

Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000 years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity...

Irbesartan, a potent and selective angiotensin II type-1 (AT1 ) receptor blocker (ARB), is one of the representative medications for the treatment of hypertension. Cytochrome P450 (CYP) 2C9 is primarily involved in the oxidation of irbesartan. CYP2C9 is highly polymorphic, and genetic polymorphism of this enzyme is the leading cause of significant alterations in the pharmacokinetics of irbesartan. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes...